MerTK as a therapeutic target in glioblastoma

  • Neuro Oncol. 2018 Jan 10;20(1):92-102. doi: 10.1093/neuonc/nox111.
Jing Wu  1 ,  Lauren N Frady  2  3 ,  Ryan E Bash  2  4 ,  Stephanie M Cohen  4 ,  Allison N Schorzman  5 ,  Yu-Ting Su  1 ,  David M Irvin  2 ,  William C Zamboni  2  5 ,  Xiaodong Wang  5 ,  Stephen V Frye  5 ,  Matthew G Ewend  2  3 ,  Erik P Sulman  6 ,  Mark R Gilbert  1 ,  H Shelton Earp  2 ,  C Ryan Miller  2  4  7
Affiliations
  • 1. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • 2. Lineberger Comprehensive Cancer Center.
  • 3. Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 4. Division of Neuropathology, Department of Pathology and Laboratory Medicine.
  • 5. Division of Pharmacotherapy and Experimental Therapeutics, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina.
  • 6. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7. Department of Neurology and Neurosciences Center.
PMID: 28605477 DOI: 10.1093/neuonc/nox111
Abstract

Background: Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.

Methods: We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.

Results: MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.

Conclusions: These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

Keywords
MerTK; glioblastoma; macrophage; microenvironment.
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